Amyloid plaque formation is found in a number of diseases including Alzheimer's Disease (AD), scrapie, bovine spongiform encephalopathy, Gerstmann-Straussler Syndrome and related transmissible spongiform encephalopathies (T'SEs). These amyloid plaques comprise protein molecules bound together in a fibrinous matrix. Other disorders, such as Creutzfeldt-Jakob's disease, are characterized by the accumulation of amyloidogenic protein without deposition of amyloid plaques. Together these groups of conditions are referred to herein as "Amyloidogenic Diseases."
Amyloidogenic diseases include a heterogeneous group of hereditary and nonhereditary disorders related by their production of amyloid-forming proteins. These disorders are often accompanied by extracellular deposition of amyloid plaques in one or more tissues. An amyloid plaque is identified by its amorphous, eosinophilic, homogeneous appearance. A unique green birefringence after Congo Red staining, fibriflar ultrastructure, and cross beta X-ray diffraction pattern are also features of amyloid plaques.
The presence of amyloid plaques in various tissue samples can indicate a vast array of diseases. Alzheimer's disease is now identified by the presence of cerebral amyloid plaques derived from beta protein. Adult Type II diabetes can be identified by the presence of the amyloidogenic protein IAPP in amyloid plaques from pancreatic islets.
Some methods of affecting amyloidogenic protein accumulation have been developed. However, no general therapy directed towards many Amyloidogenic Diseases has yet been developed.
In one study of factors affecting amyloid protein accumulation, the drugs melphalan and prednisone were compared with the known protein inhibitor colchicine. Patients treated with colchicine had a median survival of 18 months compared to a control group who survived, on average, only six months. Patients treated with melphalan and prednisone survived 25 months. This study showed no significant difference in survival between subjects in any group, although the trend favored melphalan and prednisone.
Other modes of therapy have included the use of dimethyl sulfoxide and treatment of secondary amyloid with affiylating agents. An experimental fish oil diet in mice has also been studied.
In selected patients with systemic amyloidosis and azotemia, renal transplantation has exhibited effectiveness. Normal renal function may be present for a period of time after transplantation, although amyloid plaques may subsequently develop. Three year graft survival in patients receiving primary cadaveric kidney grafts has been reported, but overall survival of patients with amyloidosis has been worse than patients undergoing transplantation for glomerulonephritis. Notwithstanding the partial success of transplantation, a non-surgical intervention would be more desireable.
In scrapie, Creutzfeldt-Jakob's disease, bovine spongiform encephalopathy, and related transmissible spongiform encephalopathies, an abnormal protease-resistant isoform of the endogenous prion protein (PrP) accumulates in the CNS and other tissues. Unlike the normal, protease-sensitive PrP (PrP-sen), the protease-resistant PrP (PrP-res) is insoluble in many detergents and can aggregate into amyloid-like plaques with high 0 -sheet content. Although the etiology of these T'SEs is not clear, evidence exists that PrP plays an important role in the pathogenesis of these diseases.
Some investigators have proposed that PrP-res is a component of the infectious agent or is itself the agent, but this issue remains highly controversial. Studies of the mechanism of PrP-res formation, the relationships of PrP-res to pathogenesis and infectivity, and potential therapies for the T'SEs would be aided greatly by the availability of a compound that selectively inhibits the accumulation of PrP-res.
The structure of Congo Red dye is shown below: ##STR1## Congo Red is known to bind amyloid plaques, including those comprised of PrP-res protein. See Prusiner et al., Cell, 35:349-358 (1.983). Congo Red has also been reported to inhibit experimental casein-induced amyloid deposition in mice (Kagan et al., Problemy Tuberkuleza, 9:72-74 (1974). However, Applicants are aware of no previous uses of Congo Red in the treatment of Amyloidogenic Diseases.
The disparate presence of amyloid formations throughout the body appears to validate the notion that amyloidosis is a widespread metabolic disease. Thus, a treatment common to all such diseases would provide tremendous benefits.